Method for normalizing insulin levels

ABSTRACT

The invention is directed to a dietary supplement which contains mannoheptulose. Mannoheptulose occurs naturally in avocado fruit. The dietary supplement and its method of use can lower serum insulin levels and lower a subject&#39;s weight. The dietary supplement in its disclosed form includes a controlled release system for mannoheptulose. The dietary supplement may also include one or more amino acids.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of co-pending U.S. applicationNo. 10/280,332, filed Oct. 25, 2002, entitled “A METHOD FOR NORMALIZINGINSULIN LEVELS, the disclosure of which is incorporated by reference inits entirety herein.

BACKGROUND OF THE INVENTION

[0002] The present invention generally relates to an oral dietarysupplement which decreases serum insulin levels. High levels of seruminsulin (i.e., hyperinsulinemia) is a major health problem.Hyperinsulinemia promotes hypertension, suppresses the release of growthhormone, and can harm the kidneys. The vascular system can be severelydamaged by prolonged exposure to high insulin levels. Excess insulin canalso increase the risk and progression of certain cancers and is acontributory factor in benign prostate enlargement.

[0003] High serum insulin is associated with the development of obesityand a large number of related health problems including degenerativejoint disease, atherosclerosis, and impotence. Specifically, obesity hasbeen associated with excess insulin production and reduced insulinsensitivity which are both risk factors for Type II diabetes. Therefore,obese individuals face a significant risk for developing Type IIdiabetes. It is possible to mitigate or control either Type II diabetesor obesity by effectively controlling the other.

[0004] There has been an increasing incidence of obesity in our societyand an absence of effective weight control. The role of hyperinsulinemiain the origin and maintenance of idiopathic obesity is well established.It is widely known in the medical community that an increase in fastinginsulin is the critical difference between thin and obese persons.Specifically, fat cannot be released from storage as long as insulin ispresent in the blood. This may be why dieting alone, i.e. caloricrestriction, has not been effective in controlling obesity. When insulinin circulating in the blood stream, the body will not releasesignificant fat stores, even when a person exercises and restricts theirfood intake. Such circumstances would only result in the loss of leanbody mass and fluid.

[0005] In normal healthy individuals, insulin blood levels fall to zerowhen the serum glucose level drops below approximately 83 mg %. In obeseindividuals, insulin blood levels rarely fall to zero. As little as onemicrounit of insulin in serum will prevent the breakdown of stored fat.

[0006] Even starvation does not bring insulin levels to normal in obesesubjects.

[0007] As people age, sensitivity of cells to insulin generallydecreases due to sedentary lifestyles, poor diet, and the natural agingprocess. The pancreatic response to this is often hyper-secretion ofinsulin. Therefore, it is difficult for people to lose a significantamount of body fat as long as they suffer from insulin overload Anoticeable effect of excess serum insulin is constant hunger. Thisresults in a vicious cycle where overeating causes more body fat toaccumulate and in turn, causes greater amounts of insulin secretion. Themost immediate and noticeable effect of too much insulin may be unwantedweight gain.

[0008] Mannoheptulose is a seven carbon sugar which is naturally foundin avocado fruit. Mannoheptulose inhibits hexokinase in a predominantlycompetitive manner. Hexokinase is an enzyme which catalyzes thephosphorylation of glucose to glucose-6-phosphate (G6P), which is thefirst reaction of glycolysis. Therefore, ingestion of mannoheptulose isa logical method of decreasing insulin serum levels.

[0009] Previously, the potential usefulness of this seven-carbonketogenated sugar has been limited by its unpleasant side effects (e.g.,diarrhea, nausea) and poor absorption on oral administration. There areproblems with unpleasant side-effects, and problems of transienthypoglycemia. Scientists have believed that orally administeredmannoheptulose was limited to the extent which it could be absorbed inman, because of its laxative effect when orally administered. Thiseffect is most likely an osmotic effect, similar to that of mannitol.Mannoheptulose has been shown to lower fasting and glucose stimulatedpeak insulin release in mammals including man.

[0010] The only oral pharmaceutical preparation available forhyperinsulinemia is diazoxide (sold under the tradename Proglycem®,which is also sold as an intravenous anti-hypertensive (sold under thetradename Hyperstat®). However, its usefulness has been limited by itssignificant side-effects and serious drug interactions. Treatment ofobese patients with diazoxide lowers insulin levels, but also dropsblood pressure dangerously and can intensify the effects ofanticoagulants. The diazoxide intravenous solution must be administeredwith great care so as to not inject it subcutaneously, intramuscularlyor into body cavities. Extravasation must be avoided because thesolution is alkaline and very irritating.

[0011] Many features, advantages, and objects of the present inventionwill become apparent to one with skill in the art upon examination ofthe detailed description. It is intended that all such features,advantages, and objects be included herein within the scope of thepresent invention.

SUMMARY OF THE PRESENT INVENTION

[0012] One embodiment of the present invention is an oral dosage formwhich includes mannoheptulose and a controlled release system. It mayoptionally include one or more amino acids.

[0013] Another embodiment of the present invention is a method forlowering serum insulin levels using the oral dosage form. An alternateembodiment of the present invention is a method for weight loss usingthe oral dosage form. In yet another embodiment of the presentinvention, the invention is a method of preparing the oral dosage form.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0014] The present invention provides a novel oral dosage form andmethod which have many uses. Possible uses include, but are not limitedto, reducing a subject's serum insulin levels and controlling obesity orotherwise affecting a subject's weight. The subject may be any animal inwhich one desires to affect a biological response or elicit therapeuticresult. It is preferred that the subject be a mammal. It is mostpreferred that the subject be human.

[0015] The dosage form includes mannoheptulose, a seven carbon sugarwhich naturally occurs in avocado fruit. It most preferably includes thedextro (i.e., right or d-) isomer of mannoheptulose. The dosage form ofthe present invention can include any amount of mannoheptulose whichwill affect a biological response or elicit a therapeutic result fromthe subject. For example, the biological response or therapeutic resultmay be to reduce fasting insulin or control a subject's weight. Therange of the amount of mannoheptulose in the oral dosage form of thepresent invention can be from approximately 1 mg-5 gm. The preferredrange is approximately 10 mg-1000 mg. The most preferred range isapproximately 50 mg-250 mg.

[0016] The dosage form of the present invention can be any dosage formthat can be administered orally and elicit a desired response or resultfrom a subject. Examples of dosage forms of the present inventioninclude, but are not limited to tablets, capsules, semisolids, liquids,solutions, suspensions, and emulsions. Tablets and capsules arepreferred dosage forms. The most preferred dosage form is a tablet.

[0017] The dosage form of the present invention includes a controlledrelease system. The controlled release system may be any system whichcan affect the dissolution or bioavailability of mannoheptulose.Possible systems include, but are not limited to slow release systems,extended release systems, delayed release systems, multi-layer tablets,semipermeable membranes, gelatin capsules, and the use of semisolids.Controlled release may possibly be achieved by changing diffusion,dissolution, ion-exchange, or osmotic pressure. Controlled release mayalso be achieved by the use of various excipients such as bindingagents, moistening agents, surfactants, disintegrants, lubricants,diluents, glidants, and adsorbents. The controlled release may also beachieved by adjusting formulation factors such as effective surface areaof the drug, compression, granule size, and coatings. A preferredcontrolled release system of the present invention is an entericcoating. The most preferred controlled release system of the presentinvention is one which uses of carboxymethylcellulose.

[0018] The oral dosage form of the present invention may optionallyinclude one or more amino acids. The amino acids provide a source ofenergy for a subject, and because they are not sugars, they do notaffect insulin or glucose serum levels. Any amino acid which provides asource of energy for a subject may be used. A possible amino acid is1-aspartic acid. The most preferred amino acid is 1-glutamic acid.

[0019] The present invention is also a method for using the oral dosageform of the present invention (i.e., the novel oral dosage form) toachieve a desired response, a desired therapeutic outcome or affect adesired therapeutic condition. One example of a method of the presentinvention is a method which uses the novel oral dosage form to decreaseserum insulin levels. Another example of a method of the presentinvention is a method which uses the novel oral dosage form to decreasea subject's weight. Another example of a method of the present inventionis a method which uses the novel oral dosage form to mitigate or controlany condition secondary to or relating to high serum insulin levels. Yetanother example of a method of the present invention is a method whichuses the novel oral dosage form to deplete a subject's stored fat. Themost preferred method of the present invention is a method which usesthe novel oral dosage form to decrease a subjects weight.

[0020] The present invention is also a method for preparing the noveloral dosage form of the present invention. A preferred is a method ofpreparation includes the step of extracting mannoheptulose from avocadofruit by ethanolic extraction. The extraction may be directly orindirectly from avocado fruit. Many varieties of avocado can be used. Itis preferred to use a variety of avocado which is inexpensive, easilyattainable, and which has a high concentration of mannoheptulose. Themost preferred varieties of avocados for use in the present inventionare Booth 7 and Lula.

[0021] All stereoisomers of the compounds of the present invention arecontemplated and within the scope of the invention, either in admixtureor in pure or substantially pure form. The definition of mannoheptuloseand amino acids according to the invention embraces all possiblestereoisomers and their mixtures. It very particularly embraces theforms and the isolated optical isomers having the specified activity.The forms can be resolved by physical methods, such as, for example,fractional crystallization, separation or crystallization ofdiastereomeric derivatives or separation by chiral columnchromatography. The individual optical isomers can be obtained from theracemates by any conventional methods.

[0022] The present invention is illustrated by the following examplesthat should not be considered limiting.

EXAMPLE 1 A. Methodology

[0023] The purpose of this study was to ascertain if excess levels ofserum insulin could be safely reduced (i.e., without inducinghyperglycemia) in a group of overweight male human subjects usingd-mannoheptulose (MH). A six-week double-blind study would alsodetermine if combining an amino acid (i.e., 1-glutamic acid) and entericcoating would enhance the bioavailability and efficacy of orald-mannoheptulose and prevent diarrhea. The amount of amino acid used was500 mg per dose.

[0024] Thirteen healthy male human subjects, aged thirty-seven tofifty-seven, each at least forty pounds overweight, underwent screeningblood testing. The Automated Chemistry Profile used included thefollowing measurements: Serum Glucose, BUN, Creatinine, BUN/CreatinineRatio, Uric Acid, Sodium, Potassium, Chloride, Carbon Dioxide, Calcium,Phosphorous, Total Protein, Albumin, Globulin, A/G Ratio, TotalBilirubin, Alkaline Phosphatase, LDH, AST, ALT, and Iron. A LipidProfile, and CBC with Differential were also measured. Tests specific tothis study included C-Peptide, Serum Insulin, and Hemoglobin A1c.

[0025] Subjects were randomly placed into two groups: “A” (Purple Caps)and “B” (Green Caps). Neither subject nor investigator knew which dosageforms were active and which were placebo. Once a week for three weeks,all subjects came to a local medical office while fasting and, stayedfor a period of at least four hours. Blood was drawn from each subjectin the fasting state, immediately following a high sugar meal, and atone and three hours after taking 500 mg. of MH. Additionally, fastingblood levels of glucose and insulin were drawn two times a week.

[0026] The intent was to cross over the patient test groups at the endof three weeks. But, the response of the group receiving activesubstance was so obvious that any attempt to continue the double-blindmethodology in secrecy was pointless. The active compound group not onlystabilized their eating patterns, but also experienced considerableweight loss.

[0027] At the end of the third week, the code was broken, confirmingthat the subjects with the dramatic response were getting the activeoral dosage form. Thereafter, all subjects were given the same activedosage form.

[0028] Prior to receiving the active oral dosage form, every subject haddemonstrated elevated C-Peptide levels and elevated glucose:insulinRatio (0.41 times glucose mg/% minus 34 equals insulin in microunits).

B. Findings and Conclusion

[0029] Compared to the baseline obtained at the beginning of the study,average levels of fasting serum insulin were 26.41% lower at the end ofstudy. Fasting serum glucose levels were an insignificant 1.52% higherat the end of the study, indicating that the significant suppression offasting insulin in response to MH did not induce an increase in serumglucose or the development of hyperglycemia.

[0030] In response to a same-day glucose challenge, serum glucose andinsulin levels increased as expected. Three hours after administeringone dose of MH, serum insulin levels were, on average, 22.4% lower thanthe baseline fasting insulin levels obtained just four hours earlier.Average glucose levels increased an insignificant 1.92%. This same-daytest of study subjects demonstrated that the immediate insulinsuppressing effect of MH does not result in an increase in serum glucoseor in the development of acute hyperglycemia.

[0031] The serum glucose averages excluded one study participant who washypoglycemic when entering the study, but became normalglycemic inresponse to using the MH compound. This desirable therapeutic benefitmay have occurred in response to the normalization of insulin metabolisminduced by the MH.

[0032] End of study C-peptide levels were only obtained on two subjects.The results showed an average reduction of 43% in C-peptide levels atthe end of the study compared to baseline, indicating a normalization ofinsulin metabolism.

[0033] All study participants reported significant weight-loss andreduction in carbohydrate craving. Since this study was designed todetermine the hematological effects of administering MH to overweighthuman males, data on weight loss was not collected. There were nohematological or symptomatic indications of toxicity in any of thesubjects. Patient compliance was high, due in part to thethree-times-a-week visits to the local medical center.

[0034] Enterically coated MH proved to be effective short-term andlong-term, in lowering elevated serum insulin. Moreover, not oneinstance of nausea or diarrhea was reported. The relatively small doseof MH can be expected to reliably lower insulin levels without inducinghyperglycemia. The combination of predictable insulin control andabsence of adverse events supports using this preparation in for weightloss. TABLE 1 Intake (FASTING) Blood Determinations C-Peptide SubjectNumber Glucose (mg./%) Insulin (uU) (ng./mL) 1-1  99 15.1 4.1 1-2 10317.8 5.4 1-3  132* 83.1* 11.9 1-4  90 12.8 4.8 1-5  88 14.3 4.5 1-6  9924.3 6.3 1-7  54* 11.1 5.8 0-1 107 23.1 5.4 0-2 107 18.7 4.5 0-3  8613.7 4.4 0-4  94 23.7 5.0 0-5 100 18.5 4.6 0-6  98 20.1 5.1

[0035] TABLE 2 High Peak (Glucose Challenge) C-Peptide Subject NumberGlucose (mg/%) Insulin (uU) (ng/mL) 1-1 127 110.6 8.4 1-2 118 44.5 8.01-3 91 18.1 4.3 1-4 179 154.3 9.6 1-5 184 174.6 — 1-6 97 83.5 — 1-7 9233.5 16.0  0-1 106 152.9 12.6  0-2 185 86.0 — 0-3 97 54.6 — 0-4 112 — —0-5 144 312 22.0  0-6 101 69.6 —

[0036] TABLE 3 One Hour Post-MH Subject Number Glucose (mg/%) Insulin(uU) C-Peptide 1-1 97 83.2 — 1-2 108 25.3 — 1-3 — — — 1-4 95 71.4 — 1-593 49.2 — 1-6 100 14.6 — 1-7 90 177.3 — 0-1 118 68.0 — 0-2 114 2.2 — 0-3100 17.1 — 0-4 Disc. Disc. Disc. 0-5 Disc. Disc. Disc. 0-6 Disc. Disc.Disc.

[0037] TABLE 4 Three Hour Post MH Subject Number Glucose (mg/%) Insulin(uU) C-Peptide 1-1 104 14.5 — 1-2 106 17.9 — 1-4 94 15.5 — 1-5 84 10.5 —1-6 92 14.3 7.9 1-7 88 12.3 — 0-1 123 12 — 0-2 111 4.0 — 0-3 80 16.1 —

[0038] TABLE 5 End Of Study Blood Levels Subject Number Glucose (mg/%)Insulin (uU) C-Peptide 1-1  95 8.4 2.2 1-2 106 17.9 — 1-5  96 8.2 — 1-6 90 12.6 — 1-7  94 7.8 3.4 0-1  98 20.1 — 0-2  127* 17.3* —

[0039] * It should be noted that with regards to Table 4, patientsamples 0-4 through 0-6 are missing. Also, with regards to Table 5,patient samples 0-3 through 0-6 are missing. These are due to patientsdropping out of the study or laboratory errors such as lost specimens.

EXAMPLE 2 A. Methodology

[0040] All study subjects had serum insulin, blood glucose, andC-peptide levels drawn. The relationship of insulin to glucose wasdetermined by the following formula:

Glucose (mg %)×0.41−34=Insulin

[0041] Thus:

83 mg % glucose×0.41=34.03−34=0.03

[0042] or, insulin vanishes from the blood at 83 mg %.

[0043] Subjects were male and females under the age of 50, who were atleast 45 pounds overweight according to the body mass index (BMI). Nonewere found to be hyperglycemic or to spill sugar in urine. All werefound to have fasting insulin levels of at least 30, and all were foundto be hyperinsulinemic with regards to the glucose:insulin ratio.Sixteen subjects were given 500 mg of d-manno-heptulose (MH) in entericcoated capsules. Sixteen subjects were given placebo in similarappearing capsules.

[0044] All subjects received doses four times a day, which were orallyingested in the presence of the investigator. Insulin and glucose levelswere drawn one hour after ingesting capsules, two hours afterwards, andfour hours afterwards. C-peptide levels were measured once a day.Patients were asked to keep meal logs, recording everything that theyingested by mouth, on a daily basis, for the duration of the study. Thesubjects and investigators were both blind to the group receiving activemedication. At the end of three weeks, the test groups were switched.The group receiving active dosage forms was switched with the groupreceiving placebo.

[0045] The initial time period was designed to be three weeks. However,four patients dropped out because they found the schedule too demanding.Nine of the control group patients expressed a desire to quit, and fourwere allowed to withdraw. The remaining twenty-four subjects completedthe six week period.

B. Findings & Conclusions

[0046] The twelve subjects designated A group were found to have beentaking the active medication. All demonstrated similar changes in bloodchemistry. Two hours after administration of the MH, insulin levels haddecreased by an average of 81%. Fasting insulin was found to be 0 (zero)in all subjects after having taken active medication for three days.Control subjects (those ingesting placebo) showed no changes inglucose:insulin ratio, or in fasting insulin levels.

[0047] All twelve active medication subjects lost weight and experiencedchanges in food preference. Average weight loss was 1.6 lbs. per day persubject, with the greatest being 1.9 lbs. per day, and the lowest being1.2 lbs. per day. Although the methodology for measurement of grams ofcarbohydrate consumed per day had not been provided, all MH recipientsreported diminished tolerance for high-sugar foods while on medication.

[0048] When the original twelve active principle patients were switchedto placebo, the insulin suppressing action continued to be seen foreleven days, on average. Weight loss continued for as long as patientswere followed, although average loss decreased to 0.7 lbs. per day. Atthe conclusion of the twenty-one days of placebo ingestion, the originalMH group was still reporting diminished desire for and tolerance ofsugar.

[0049] Changing from placebo to MH, the control group showed a fasterresponse to MH than did the original group. Fasting insulin had beenrestored to 0 (zero) by the middle of the second day of MHadministration, after six doses had been taken. This was four dosesfaster than the original group. Weight loss also was greater, withaverage per day losses over the twenty-one days at 2.2 lbs.

[0050] We conclude that enterically coated d-mannoheptulose begins toeffectively lower plasma insulin levels within two hours ofadministration. This effect is sustained by dosing every six hours and,three days of continuous ingestion affects changes in food preferencethat contribute to the drug's efficacy. Discontinuation of MH does notresult in immediate reversion to baseline.

[0051] It should be emphasized that the foregoing description andexamples have been presented for purpose of providing a clearunderstanding of the invention. The description is not intended to beexhaustive or to limit the invention to the precise examples disclosed.Obvious modifications or variations by one with skill in the art arepossible in light of the above teachings without departing from thespirit and principles of the invention. All such modifications andvariations are intended to be within the scope of the present invention.

1. A solid oral dosage form to be swallowed, wherein said dosage formcomprises mannoheptulose and a controlled release system.
 2. The oraldosage form of claim 1, wherein said controlled release system is adelayed release system.
 3. The oral dosage form of claim 1, wherein saidcontrolled release system is a sustained release system.
 4. The oraldosage form of claim 1, wherein said controlled release system comprisescarboxymethylcellulose.
 5. A solid oral dosage form to be swallowed,wherein said oral dosage form comprises mannoheptulose, a controlledrelease system, and one or more amino acids.
 6. The oral dosage form ofclaim 5, wherein one amino acid is glutamic acid.
 7. The oral dosageform of claim 5, wherein one amino acid is aspartic acid.
 8. The oraldosage form of any one of claims 1-7, wherein said oral dosage formcomprises 10 mg-1000 mg of mannoheptulose.
 9. The oral dosage form ofany one of claims 1-7, wherein said oral dosage form comprises 50 mg-250mg of mannoheptulose.
 10. (canceled)
 11. (canceled)
 12. (canceled) 13.(canceled)
 14. (canceled)